KR102268210B1 - Process for manufacturing glatiramer acetate product - Google Patents

Abstract

This patent provides a process for the preparation of a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable container comprising the steps of: (i) obtaining an aqueous pharmaceutical solution of glatiramer acetate and mannitol; (ii) filtering the aqueous pharmaceutical solution at a temperature greater than 0° C. to 17.5° C. to prepare a filtrate; and (iii) filling a suitable vessel with the filtrate obtained after performing step (ii) so as to prepare a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable vessel. This patent further provides an aqueous pharmaceutical solution comprising 40 mg/ml of glatiramer acetate and 40 mg/ml of mannitol, wherein the aqueous pharmaceutical solution a) has a viscosity in the range of 2.0-3.5 cPa; or b) has an osmolality in the range of 275-325 mosmol/Kg. The patent also provides prefilled syringes, autoinjectors and methods of treating human patients.

Description

GLATIRAMER ACETATE PRODUCT PROCESS FOR MANUFACTURING GLATIRAMER ACETATE PRODUCT

This application claims priority to U.S. Regular Application No. 14/608,126, filed January 28, 2015, the entire contents of which are incorporated herein by reference.

Throughout this application, various publications are referred to by first author and year of publication. Full bibliographic information for these publications is presented in the references section immediately before the claims. The disclosures of these documents and publications mentioned herein are incorporated in their entirety by reference into this application in order to more fully describe the state of the art to which this invention pertains.

background of the invention

The active ingredient of Copaxone ^® , glatiramer acetate (GA), is a four naturally occurring naturally occurring acid that is L-glutamic acid, L-alanine, L-tyrosine, and L-lysine, with average molar fractions of 0.141, 0.427, 0.095, and 0.338, respectively. It consists of an acetate salt of a synthetic polypeptide containing amino acids. The peak average molecular weight of glatiramer acetate is between 5,000 and 9,000 daltons. Glatiramer acetate is identified by a specific antibody (Copaxone, Food and Drug Administration Approved Labeling (Reference ID: 3443331) [online], TEVA Pharmaceutical Industries Ltd., 2014 [Retrieved Dec. 24, 2014], Retrieved on the Internet : <URL: www.accessdata.fda.gov/drugsatfda_docs/label/2014/020622s 089lbl.pdf>).

Chemically, glatiramer acetate refers to a polymer of L-glutamic acid with L-alanine, L-lysine and L-tyrosine, acetate (salt). Its structural formula is:

Copaxone ^® is a clear, colorless to pale yellow, sterile, non-pyrogenic solution for subcutaneous injection. Each 1 mL Copaxone ^® solution contains 20 mg or 40 mg of GA, active ingredient, and 40 mg of mannitol. The pH of the solution is approximately 5.5-7.0. ^{Copaxone ®} 20mg/mL in a prefilled syringe (PFS) is an approved product, and its safety and efficacy are supported by over 20 years of clinical research and over 10 years of post-marketing experience. Copaxone ^® 40mg/mL in PFS was developed as a novel formulation of the active ingredient GA. Copaxone ^® 40 mg/mL is a prescription drug used for the treatment of humans with a relapsing form of multiple sclerosis (Copaxone, Food and Drug Administration Approved Labeling (Reference ID: 3443331) [online], TEVA Pharmaceutical Industries Ltd., 2014 [2014] Retrieved December 24, Retrieved from the Internet: <URL:www.accessdata.fda.gov/drugsatfda_docs/label/2014/020622s0891bl.pdf>).

It is an object of the present invention to provide an improved process for the preparation of GA drug products.

Summary of the invention

This patent provides a process for the preparation of a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable container comprising the steps of:

(i) obtaining an aqueous pharmaceutical solution of glatiramer acetate and mannitol;

(ii) filtering the aqueous pharmaceutical solution at a temperature greater than 0° C. to 17.5° C. to prepare a filtrate; and

(iii) filling a suitable vessel with the filtrate obtained after performing step (ii) so as to prepare a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable vessel.

This patent also provides a prefilled syringe prepared by the method of the present invention containing 40 mg of glatiramer acetate and 40 mg of mannitol.

This patent also states that aqueous pharmaceutical solutions are

a) having a viscosity in the range of 2.0-3.5 cPa; or

b) having an osmolality in the range of 275-325 mosmol/Kg,

Further provided is an aqueous pharmaceutical solution comprising 40 mg/ml of glatiramer acetate and 40 mg/ml of mannitol.

This patent also provides a prefilled syringe containing 1 ml of an aqueous pharmaceutical solution prepared by the method of the present invention.

This patent also provides an autoinjector comprising a prefilled syringe made by the method of the present invention.

Aspects of the present invention provide for the treatment of human patients using a prefilled syringe of the present invention, using an aqueous pharmaceutical solution of the present invention, or using an automatic injector of the present invention at a dose of 40 mg/ml gla per week. A method of treating a human patient suffering from a relapsing form of multiple sclerosis comprising administering to the human patient three subcutaneous injections of tiramer acetate.

Figure 1. Schematic illustration of the filtration process by means of a cooled receiving vessel and filter housing.
Figure 2. Schematic illustration of the filtration process by means of a heat exchanger and a cooled filter housing.
Figure 3. Pressure recorded for Experiment No. 1. * At controlled room temperature, the filtration of the GA solution was stopped and the residual solution was transferred to a cooled receiving vessel.
Figure 4. Pressure recorded for experiment number 2. *Pauses of 3 hours and 5 hours for filtered GA solutions at controlled room temperature and reduced temperature, respectively. ** 10 hour pause for both GA solutions. *** Filtration of the GA solution was stopped at controlled room temperature. The residual GA solution was filtered at reduced temperature.
Figure 5. Pressure recorded for Experiment No. 3.
Figure 6. Schematic illustration of the filtration process with a cooled compounding vessel and a cooled filter housing on both filter A and filter B.
Figure 7. Schematic illustration of the filtration process by means of a heat exchanger and a cooled filter housing on both filter A and filter B.
Figure 8. Schematic illustration of the filtration process with a cooled filter housing exclusively on filter B.
Figure 9. Schematic illustration of the filtration process with a cooled filter housing in both filter A and filter B.
Figure 10. Schematic illustration of the filtration process by means of a cooled compounding vessel.
11. Schematic illustration of the filtration process with a cooled receiving vessel.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation of a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable container comprising the steps of:

(i) obtaining an aqueous pharmaceutical solution of glatiramer acetate and mannitol;

(ii) filtering the aqueous pharmaceutical solution at a temperature greater than 0° C. to 17.5° C. to prepare a filtrate; and

(iii) filling a suitable vessel with the filtrate obtained after performing step (ii) so as to prepare a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable vessel.

In some embodiments filtration step (ii) comprises filtering the aqueous pharmaceutical solution through a first filter, or a first filter and a second filter.

In some embodiments the method further comprises reducing the temperature of the second filter to a temperature of greater than 0 °C to 17.5 °C.

In some embodiments the method further comprises reducing the temperature of the aqueous pharmaceutical solution to a temperature of greater than 0° C. to 17.5° C. prior to passing through the second filter.

In some embodiments filtering step (ii) further comprises receiving the filtered aqueous pharmaceutical solution through a first filter in a receiving vessel.

In some embodiments the method further comprises reducing the temperature of the aqueous pharmaceutical solution to a temperature of greater than 0° C. to 17.5° C. after leaving the receiving vessel and prior to entering the second filter.

In some embodiments the method further comprises reducing the temperature of the aqueous pharmaceutical solution to a temperature of greater than 0° C. to 17.5° C. while in the receiving vessel.

In some embodiments the method further comprises reducing the temperature of the first filter to a temperature of greater than 0 °C to 17.5 °C.

In some embodiments the method further comprises reducing the temperature of the aqueous pharmaceutical solution to a temperature of greater than 0° C. to 17.5° C. prior to passing through the first filter.

In some embodiments obtaining step (i) comprises combining the aqueous pharmaceutical solution in a compounding vessel.

In some embodiments the method further comprises reducing the temperature of the aqueous pharmaceutical solution to a temperature of greater than 0° C. to 17.5° C. after leaving the compounding vessel and before entering the first filter.

In some embodiments the method further comprises reducing the temperature of the aqueous pharmaceutical solution to a temperature of greater than 0° C. to 17.5° C. within the compounding vessel.

In some embodiments the aqueous pharmaceutical solution is passed through the second filter at a rate of 3-25 liters/hour.

In some embodiments the aqueous pharmaceutical solution is passed through the second filter, preferably at a rate of 3-22 liters/hour.

In some embodiments the aqueous pharmaceutical solution is more preferably passed through the second filter at a rate of 3-15 liters/hour.

In some embodiments the aqueous pharmaceutical solution is more preferably passed through the second filter at a rate of 3-10 liters/hour.

In some embodiments the pressure during the filtration step (ii) and the pressure during the filling step (iii) are maintained below 5.0 bar.

In some embodiments the pressure during the filtration step (ii) and the pressure during the filling step (iii) are preferably kept below 3.0 bar.

In some embodiments the pressure during the filtration step (ii) and the pressure during the filling step (iii) are maintained below 2.0 bar.

In some embodiments the temperature of the aqueous pharmaceutical solution is between 0°C and 14°C, or the temperature of the aqueous pharmaceutical solution is reduced to a temperature of between 0°C and 14°C.

In some embodiments the temperature of the aqueous pharmaceutical solution is between 0°C and 12°C, or the temperature of the aqueous pharmaceutical solution is reduced to a temperature of between 0°C and 12°C.

In some embodiments the temperature of the aqueous pharmaceutical solution is 2°C-12°C, or the temperature of the aqueous pharmaceutical solution is reduced to 2°C-12°C.

In some embodiments the temperature of the aqueous pharmaceutical solution is 4°C-12°C, or the temperature of the aqueous pharmaceutical solution is reduced to 4°C-12°C.

In some embodiments the filtration is performed using a sterile filter having a pore size of 0.2 μm or less, and the first filter, the second filter, or both filters are sterile filters having a pore size of 0.2 μm or less.

In some embodiments the pharmaceutical formulation in a suitable container is an aqueous pharmaceutical solution comprising 20 mg/ml of glatiramer acetate and 40 mg/ml of mannitol.

In some embodiments the pharmaceutical formulation in a suitable container is an aqueous pharmaceutical solution comprising 40 mg/ml of glatiramer acetate and 40 mg/ml of mannitol.

In some embodiments the pharmaceutical formulation in a suitable container is an aqueous pharmaceutical solution having a pH in the range of 5.5-7.0.

In some embodiments the pharmaceutical formulation in a suitable container is an aqueous pharmaceutical solution that is a sterile aqueous solution sterilized by filtration, and is an aqueous pharmaceutical solution that has not been subjected to heat, chemical, or radiation exposure.

In some embodiments the pharmaceutical formulation is a lyophilized powder of glatiramer acetate and mannitol.

In some embodiments the method further comprises filling the filtrate into a suitable vessel to form a lyophilized powder of glatiramer acetate and mannitol in the suitable vessel followed by lyophilization.

In some embodiments suitable containers are syringes, vials, ampoules, cartridges or infusions.

In some embodiments a suitable container is a syringe.

In some embodiments the syringe contains 1 ml of an aqueous pharmaceutical solution.

The present invention provides a prefilled syringe prepared by the method of the present invention containing 40 mg of glatiramer acetate and 40 mg of mannitol.

According to an embodiment of the prefilled syringe disclosed herein, the prefilled syringe contains 1 ml of an aqueous pharmaceutical solution of glatiramer acetate at 40 mg/ml and mannitol at 40 mg/ml.

According to an embodiment of the prefilled syringe disclosed herein, the aqueous pharmaceutical solution comprises:

a) having a viscosity in the range of 2.0-3.5 cPa; or

b) has an osmolality in the range of 270-330 mosmol/Kg.

According to an embodiment of the prefilled syringe disclosed herein, the aqueous pharmaceutical solution comprises:

a) has a viscosity in the range of 2.2-3.0 cPa; or

b) has an osmolality in the range of 275-325 mosmol/Kg.

* The present invention is an aqueous pharmaceutical solution

a) having a viscosity in the range of 2.0-3.5 cPa; or

b) having an osmolality in the range of 275-325 mosmol/Kg,

An aqueous pharmaceutical solution comprising 40 mg/ml of glatiramer acetate and 40 mg/ml of mannitol is provided.

According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution has a viscosity in the range of 2.0-3.5 cPa.

According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution has a viscosity in the range of 2.61-2.92 cPa.

According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution has an osmolality in the range of 275-325 mosmol/Kg.

According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution has an osmolality in the range of 300-303 mosmol/Kg.

According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution comprises glatiramer acetate having a viscosity in the range of 2.3-3.2 cPa.

According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution comprises glatiramer acetate having a viscosity in the range of 2.6-3.0 cPa.

According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution comprises glatiramer acetate having an osmolality in the range of 290-310 mosmol/Kg.

According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution comprises glatiramer acetate having an osmolality in the range of 295-305 mosmol/Kg.

According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution has a pH in the range of 5.5-7.0.

* The present invention provides a prefilled syringe containing 1 ml of the aqueous pharmaceutical solution prepared by the present invention.

The present invention provides an autoinjector comprising a prefilled syringe made according to the present invention.

The present invention provides glatiramer at a dose of 40 mg/ml per week using a prefilled syringe of the present invention, using an aqueous pharmaceutical solution of the present invention, or using an autoinjector of the present invention to treat human patients. A method of treating a human patient suffering from a relapsing form of multiple sclerosis comprising administering to the human patient three subcutaneous injections of acetate is provided.

In some embodiments, the human patient has relapsing-remitting multiple sclerosis.

In some embodiments, the human patient has experienced a first clinical episode and has MRI characteristics consistent with multiple sclerosis.

The present invention provides a process for the preparation of a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable container comprising the steps of:

(i) obtaining an aqueous pharmaceutical solution of glatiramer acetate and mannitol;

(ii) filtering the aqueous pharmaceutical solution at a temperature greater than 0° C. to 17.5° C. to prepare a filtrate; and

(iii) filling a suitable vessel with the filtrate obtained after performing step (ii) so as to prepare a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable vessel.

In one embodiment filtration step (ii) comprises filtering the aqueous pharmaceutical solution through a first filter and a second filter.

In one embodiment, obtaining step (i) comprises combining the aqueous pharmaceutical solution in a compounding vessel.

In one embodiment, the method further comprises reducing the temperature of the aqueous pharmaceutical solution in the compounding vessel to a temperature of greater than 0°C to 17.5°C.

In one embodiment, the method further comprises reducing the temperature of the first filter to a temperature of greater than 0 °C to 17.5 °C.

In one embodiment, the method further comprises reducing the temperature of the second filter to a temperature of greater than 0 °C to 17.5 °C.

The present invention provides a process for the preparation of a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable container comprising the steps of:

(i) obtaining an aqueous pharmaceutical solution of glatiramer acetate and mannitol;

(ii) filtering the aqueous pharmaceutical solution at a temperature greater than 0° C. to 17.5° C. to prepare a filtrate; and

(iii) filling a suitable vessel with the filtrate obtained after performing step (ii) so as to prepare a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable vessel.

In one embodiment, filtration step (ii) comprises filtering the aqueous pharmaceutical solution through a first filter and a second filter.

In one embodiment, obtaining step (i) comprises combining the aqueous pharmaceutical solution in a compounding vessel.

In one embodiment, the method further comprises reducing the temperature of the aqueous pharmaceutical solution to a temperature of greater than 0° C. to 17.5° C. after leaving the compounding vessel and before entering the first filter.

In one embodiment, the method further comprises reducing the temperature of the first filter to a temperature of greater than 0 °C to 17.5 °C.

In one embodiment, the method further comprises reducing the temperature of the second filter to a temperature of greater than 0 °C to 17.5 °C.

The present invention provides a process for the preparation of a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable container comprising the steps of:

(i) obtaining an aqueous pharmaceutical solution of glatiramer acetate and mannitol;

(ii) filtering the aqueous pharmaceutical solution at a temperature greater than 0° C. to 17.5° C. to prepare a filtrate; and

(iii) filling a suitable vessel with the filtrate obtained after performing step (ii) so as to prepare a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable vessel.

In one embodiment, filtration step (ii) comprises filtering the aqueous pharmaceutical solution through a first filter and a second filter.

In one embodiment, the method further comprises reducing the temperature of the second filter to a temperature of greater than 0 °C to 17.5 °C.

The present invention provides a process for the preparation of a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable container comprising the steps of:

(i) obtaining an aqueous pharmaceutical solution of glatiramer acetate and mannitol;

(ii) filtering the aqueous pharmaceutical solution at a temperature greater than 0° C. to 17.5° C. to prepare a filtrate; and

(iii) filling a suitable vessel with the filtrate obtained after performing step (ii) so as to prepare a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable vessel.

In one embodiment, filtration step (ii) comprises filtering the aqueous pharmaceutical solution through a first filter and a second filter.

In one embodiment, the method further comprises reducing the temperature of the first filter to a temperature of greater than 0 °C to 17.5 °C.

In one embodiment, the method further comprises reducing the temperature of the second filter to a temperature of greater than 0 °C to 17.5 °C.

The present invention provides a process for the preparation of a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable container comprising the steps of:

(i) obtaining an aqueous pharmaceutical solution of glatiramer acetate and mannitol;

(ii) filtering the aqueous pharmaceutical solution at a temperature greater than 0° C. to 17.5° C. to prepare a filtrate; and

(iii) filling a suitable vessel with the filtrate obtained after performing step (ii) so as to prepare a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable vessel.

In one embodiment, filtration step (ii) comprises filtering the aqueous pharmaceutical solution through a first filter and a second filter.

In one embodiment, obtaining step (i) comprises combining the aqueous pharmaceutical solution in a compounding vessel.

In one embodiment, the method further comprises reducing the temperature of the aqueous pharmaceutical solution in the compounding vessel to a temperature of greater than 0°C to 17.5°C.

The present invention provides a process for the preparation of a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable container comprising the steps of:

(i) obtaining an aqueous pharmaceutical solution of glatiramer acetate and mannitol;

(ii) filtering the aqueous pharmaceutical solution at a temperature greater than 0° C. to 17.5° C. to prepare a filtrate; and

(iii) filling a suitable vessel with the filtrate obtained after performing step (ii) so as to prepare a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable vessel.

In one embodiment, filtration step (ii) comprises filtering the aqueous pharmaceutical solution through a first filter and a second filter.

In one embodiment, filtration step (ii) further comprises receiving the filtered aqueous pharmaceutical solution through a first filter in a receiving vessel.

In one embodiment, the method further comprises reducing the temperature of the aqueous pharmaceutical solution to a temperature of greater than 0° C. to 17.5° C. while in the receiving vessel.

automatic injection device

The mechanical operation of automatic injection support devices is described in European Application Publication Nos. EP0693946 and U.S. Pat. may be prepared according to the disclosure of Patent No. 7,855,176.

All combinations of the various elements described herein are within the scope of the present invention.

Justice

"Glatiramer acetate" as used herein is a complex mixture of acetate salts of synthetic polypeptides containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine. The peak average molecular weight of glatiramer acetate is between 5,000 and 9,000 daltons. Chemically, glatiramer acetate represents a polymer of L-glutamic acid with L-alanine, L-lysine and L-tyrosine, acetate (salt). Its structural formula is:

A “glatiramer acetate drug substance” as used herein is the glatiramer acetate active ingredient prior to being formulated into a glatiramer acetate drug product.

A “glatiramer acetate drug product” as used herein is a formulation for pharmaceutical use containing a glatiramer acetate drug substance. Copaxone ^® is Copaxone, Food and Drug Administration Approved Labeling (Reference ID: 3443331) [online], TEVA Pharmaceutical Industries Ltd., 2014 [Retrieved December 24, 2014], the contents of which are hereby incorporated by reference, Retrieved on the Internet : A commercial glatiramer acetate drug product manufactured by TEVA Pharmaceutical Industries Ltd. (Israel) described in <URL:www.accessdata.fda.gov/drugsatfda_docs/label/2014/020622s0891bl.pdf>. Copaxone ^® can be used at a dose of 20 mg/mL once a day and/or at a dose of 40 mg/ml three times a week.

A “sterilizing filter” as used herein is a filter having a pore size of 0.2 μm or less that will effectively remove microorganisms.

By all ranges disclosed herein, it is meant that all hundredths, tenths, and whole numbers within the ranges are specifically disclosed as part of this invention. Thus, for example, 1 mg to 50 mg is 1.1, 1.2 ... 1.9; and 2, 3 ... 49 mg unit amounts are included as embodiments of the present invention.

While the present invention will be better understood by reference to the following experimental details, those skilled in the art will readily recognize that the specific experiments set forth in detail are merely illustrative of the invention, as more fully set forth in the claims that follow. will understand

Experiment Details

Way

Glatiramer Acetate (GA) Injection 40 mg/mL in a prefilled syringe (GA Injection 40mg/mL in PFS or Copaxone ^® 40mg/mL) is also available in the marketed product Copaxone ^® 20mg/mL solution for injection in a prefilled syringe. It has been developed as a new formulation of the active ingredient glatiramer acetate used. Copaxone ^® 40 mg/mL should be administered by subcutaneous injection 3 times per week in patients with relapsing-remitting multiple sclerosis. The new formulation is based on the formulation of ^{a commercially available Copaxone ®} 20 mg/mL solution for injection in a prefilled syringe. Copaxone ^® 20mg/mL is an approved product, and its safety and efficacy are supported by over 20 years of clinical research and over 10 years of post-marketing experience. The only difference between the formulations is the doubling of the amount of active substance used, which results in a solution with doubling the concentration of glatiramer acetate (40 mg/mL vs. 20 mg/mL). The amount of mannitol in both Copaxone ^® formulations does not change (40 mg/mL).

The composition of Copaxone ^® 20 mg/mL and Copaxone ^® 40 mg/mL is detailed in Table 1.

Copaxone ^® 20mg/mL and Copaxone ^® Composition of 40 mg/mL ingredient
Copaxone ^® 20mg/mL
Copaxone ^® 40mg/mL Content/mL glatiramer acetate ¹ 20.0mg 40.0mg Mannitol USP/Ph.Eur. 40.0mg 40.0mg water for injection
USP/Ph.Eur/JP Appropriate amount until 1.0mL Appropriate amount until 1.0mL

1. Calculated for dry basis and 100% assay

A study was ^{conducted to demonstrate that the formulation of Copaxone ®} 40 mg/mL, its preparation method and chemical, biological and microbiological properties are suitable for commercialization. A study was also conducted to confirm the stability of the proposed container closure system for packaging ^{Copaxone ® 40 mg/mL.}

Mannitol is the ^{chosen isotonic agent for initially formulated Copaxone ®} (lyophilized product, reconstituted prior to administration), which is also a bulking agent. ^{When the currently marketed ready-to-use formulation of Copaxone ®} 20mg/mL solution for injection into a prefilled syringe was developed, mannitol was also used as an osmomodulator in this formulation. Eventually, when a new 40 mg/mL formulation was developed based on the ^{Copaxone ® 20 mg/mL formulation, mannitol remained as an osmoregulator.}

Mannitol is used extensively in parenteral formulations as an osmolality agent. It is freely soluble in water and stable in aqueous solution. The mannitol solution can be sterilized by filtration. In solution, mannitol is unaffected by atmospheric oxygen in the absence of a catalyst. The concentration of mannitol in Copaxone ^® 40 mg/mL is 40 mg/mL. Maintaining the mannitol concentration within Copaxone ^® 40 mg/mL results in an essentially isotonic solution.

Water for injection (WFI) is the most widely used solvent and an inert vehicle in parenteral formulations. Water is chemically stable in all physical states. It is the basis of many biological organisms, and its stability in pharmaceutical formulations is unquestioned.

Example 1

The preparation method of Copaxone ^® 40mg/mL includes:

Combining a bulk solution of GA and mannitol in water for injection (WFI).

A step of sterile filtration of the bulk solution to produce a sterile GA solution of the bulk.

· Aseptic filling and stoppering of the sterile bulk solution into the syringe barrel.

· Inspection and final assembly of filled syringes.

Initially, filtration of the bulk solution from the compounding vessel was carried out through a continuous filter consisting _{of two continuous sterile filters (the filters designated A 1} and A _{2 respectively) into the receiving vessel.} From the receiving container it is transferred to an intermediate container in the filling device and further transferred via the dosing pump and needle to the prefilled syringe. However, due to the Health Authority's request to place the sterile filter as close as possible to the fill point, the second sterile filter was moved between the receiving and intermediate containers. In the current filtration train, the first sterile filter was designated Filter A and the relocated second sterile filter was designated Filter B. See Figure 1.

^{All processing steps of the new Copaxone ®} 40mg/mL formulation were originally performed at controlled room temperature, in accordance with the approved method for the Copaxone ^{® 20mg/mL formulation.} However, filtration of the high concentration solution resulted in pressure build-up on the second filter, filter B. Despite the pressure increase observed on filter B, a high quality drug product could be obtained by filtration of GA 40 mg/mL at controlled room temperature as confirmed by the release and stability data. Nevertheless, there is a need for an improved filtration process that prevents build-up on the secondary filter.

The flow rate for a fluid can be defined by the pressure difference and can be regulated inversely by the viscosity. Viscosity is also generally inverse with respect to temperature (Meltzer and Jornitz, Filtration and Purification in the Biopharmaceutical Industry , Second Edition, CRC Press, 2007, page 166). Increasing the temperature of the solution will generally decrease the viscosity, thereby increasing the flow rate.

In an attempt to solve the pressure build-up problem on the second filter, the temperature conditions of the filtration were raised above the controlled room temperature. Although the viscosity was reduced, the filterability was reduced, resulting in unsuccessful attempts.

The following studies were conducted:

Filter validation studies: determination of ranges for manufacturing parameters related to sterile filter A and sterile filter B of bulk solutions, as well as confirmation of filter compatibility with drug products.

· Filtration process: selection of the most suitable sterile filtration conditions for the manufacturing method and quality of the drug product.

Copaxone ^® 20mg/mL and Copaxone ^® Filter used for 40 mg/mL production

The ^{method for preparing Copaxone ®} 40 mg/mL was based on the method used for the preparation of ^{a commercially available Copaxone ®} 20 mg/mL solution for injection in prefilled syringes. Therefore, the same filter used for filtration of the commercial product was used.

In order to effectively remove microorganisms, two sterile filters each having a pore size of 0.2 μm or less were used. Sterilization is achieved only by filtration using a sterile filter without the use of other methods, eg, sterilization is achieved without the use of heat, chemical, or radiation exposure.

Filter validation studies - identification and establishment of parameters related to filter suitability and sterile filtration

The following tests were performed to confirm filter effectiveness:

Extractables Test - Evaluate extractables released from the filter upon steam sterilization and their removal from the filter by the model solvent, thus the volume discarded after filtration through filter B prior to the start of aseptic filling.

Compatibility/Adsorption Test—Filter B was tested prior to the start of aseptic filling to evaluate the chemical compatibility of GA 20 mg/mL and GA 40 mg/mL solutions with filter material and their degree of adsorption to the filter, thus providing an assay within the specification. Evaluate the volume discarded after filtration through.

· Residual effect - to confirm that no significant residual GA 20mg/mL or GA 40mg/mL solution that could affect the integrity test after use remains on the filter after filtration.

· Bacterial challenge - to ensure that the filtration process does not affect the ability of the filter to provide a sterile solution.

The test was performed using maximum pressure (up to 5.0 bar). The validation study demonstrated that the selected filtration system can provide high quality Copaxone ^® 20 mg/mL and Copaxone ^® 40 mg/mL.

Given the rigorously well-defined operating and equipment parameters of the GA 40 mg/mL solution filtration process, measures have been developed to mitigate the potential for pressure build-up by reducing the filtration temperature.

Without much expectation, it was decided to test the filtration process of a 40 mg/mL sterile bulk solution of GA through filter B under reduced temperature conditions, using the same filter and filtration train for filtration at controlled room temperature.

Therefore, experiments were conducted to compare the filtration of a 40 mg/mL sterile bulk solution of GA through filter B under reduced temperature and controlled room temperature in a manufacturing environment and to ascertain that there was no difference with respect to the quality and stability profile of the filtered solution. carried out. In all experiments, sterile bulk solutions were prepared according to standard formulation and filtration trains (see FIG. 1 ) and filtered through two filters: Filter A and Filter B.

The experiment was tested with two different cooling techniques (cooled receiving vessel and heat exchanger) using cooled filters. The study is schematically illustrated in FIGS. 1 and 2 . Further details of these experiments and their results are provided later.

filtration process - Experiment number 1

The purpose of Experiment No. 1 was to compare the filterability of batches of bulk solutions maintained and filtered through Filter B under controlled room temperature or reduced temperature conditions (cooled by a double-jacketed receiving vessel and a cooled Filter B housing). will be.

The study is schematically illustrated in FIG. 1 . The experimental design and results obtained are summarized in Table 2 and FIG. 3 .

Experimental design and results for Experiment No. 1. Experiment Overview reduced temperature filtration controlled room temperature filtration combination According to standard manufacturing procedures ¹ holding time in the receiving vessel 13 hours 13 hours The temperature of the solution maintained in the receiving vessel 6.6-10.7℃ ² 17.8-24.6℃ ^{Scheme therapy 3} of filtration through filter B intermittent filtration
Stage I - Filtration of about 10 liters of bulk solution followed by 5 filtration steps of about 50 minutes each with a pause followed by a 5 hour pause.
Stage II - Filtration of about 10 liters of bulk solution followed by 4 filtration steps, each with a pause of about 50 minutes followed by a pause of about 10 hours.
Step III- Filtration of the residual solution. Total volume of filtered bulk solution About 125L.
Filtration is complete. About 85L.
Filtration was stopped due to pressure build-up on filter B.

1 One bulk solution was prepared and divided into two parts. Bulk solution size: 230L. Filtration of the solution at controlled room temperature was stopped after 85 L was pushed through the filter due to the increased pressure and the residual solution was transferred to a cooled receiving vessel.

2 Increase the temperature (14.9° C.) once during filtration after addition of the residual solution maintained at ambient temperature.

3 filtrations were performed simultaneously.

Surprisingly, filtration at reduced temperature allowed filtration to complete without the pressure increase associated with filtration at controlled room temperature.

Example 2

Filtration Process - Experiment No. 2

The first objective of Experiment No. 2 was whether local cooling of a 40 mg/mL solution of GA using a heat exchanger (HE) could improve the filterability through the cooled filter B compared to the filterability of the same bulk solution at controlled room temperature. is to evaluate

The second objective of Experiment No. 2 is to confirm that there is no difference in the quality of syringe-filled drug products at controlled room temperature and syringe-filled drug products at reduced temperature.

Cooling by a heat exchanger has been evaluated to be much easier to see in steam sterilization than using a double jacketed containment vessel. HE was placed between the receiving vessel and filter B. Consequently, in contrast to Experiment No. 1 (the solution was filtered through filter A and then cooled by a double jacketed receiving vessel and kept cool before filtering through filter B), the solution in this experiment was filtered through filter B. was maintained at controlled room temperature prior to filtration of the locally cooled GA solution (by HE).

The study is schematically illustrated in FIG. 2 . The experimental design and results obtained are summarized in Table 3. The pressures observed during the course of the filling process of Experiment No. 2 are shown in FIG. 4 .

Experimental Design and Results for Experiment No. 2 Experiment Overview reduced temperature filtration controlled room temperature filtration combination According to standard manufacturing procedures ¹ Filtration with receiving vessel Filter all of the bulk solution through filter A into a receiving vessel maintained at a controlled room temperature. The temperature of the solution maintained in the receiving vessel controlled room temperature holding time in the receiving vessel 19 hours Scheme therapy of filtration through filter B The solution is locally cooled as it is transported through the HE and filtered through cooled filtration B. Three successive filtration and filling steps.
About 3 hours rest period between Phase I and Phase II and about 10 hour rest period between Phase II and Phase III. The solution is filtered through filter B at controlled room temperature. Three successive filtration and filling steps.
About a 5 hour rest period between Phase I and Phase II and an approximately 10 hour rest period between Phase II and Phase III. Temperature of solution transmitted through HE 6.4-12℃ HE is not used Filtration time through filter B ² 24 hours 19 hours Temperature of solution transferred through filter B 5.7-8.8℃ ambient temperature Total volume of bulk solution filled with filtration and syringe 154L 63L ³ Storage conditions during stability studies Long term (2-8℃)
Accelerated (25°C/60% RH) - 6 months complete
Stress (40℃/75% RH) - 3 months complete Stability data Stability data show that the drug product has a similar stability profile when filtered under controlled room temperature or reduced temperature conditions. Both filtration processes show similar impurity profiles.

1 One bulk solution was prepared and divided into two parts. Bulk solution size: 230 liters.

2 Both filtration processes (reduced and controlled room temperature) were performed simultaneously for comparison. Filtration in each step was carried out at controlled room temperature followed by filtration at reduced temperature.

3 At a controlled room temperature, the filtration of the solution was stopped due to an increase in pressure and the remaining solution was filtered at a reduced temperature.

Example 3

Filtration Process - Experiment No. 3

One objective of Experiment No. 3 was to determine whether cooling of a GA 40mg/mL bulk solution prior to filtration using HE and a cooled filter housing could filter and fill batches of 130L size within various manufacturing regimens. .

Another objective of Experiment No. 3 was to evaluate the effect of holding time at various stages of the manufacturing process on the filterability of GA 40 mg/mL.

Another objective of Experiment 3 was that a locally cooled 40 mg/mL solution of GA filtered through filter B was obtained from a 40 mg/mL solution of GA filtered through filter B at controlled room temperature conditions with respect to certain parameters and limitations. It is to prove with a high level of verification that there is no difference in the stability profile and quality thereof.

A series of three batches of bulk solutions prepared at various regimens were prepared. Each bulk solution was prepared from the same combination of three identical batches of drug substance.

The experimental design and results are summarized in Table 4.

Experimental Design and Results for Experiment No. 3 Experiment Overview reduced temperature filtration controlled room temperature filtration reduced temperature filtration controlled room temperature filtration batch number A A-2 ¹ B C combination standard formulation standard formulation standard formulation standard formulation batch size First 130L from Bulk Solution A Residual 50L from bulk solution A 180L 180L Holding time in the mixing container ² 4 hours 4 hours (same bulk solution as A) 8 hours 3.5 hours Holding time in the receiving vessel ³ 1.5 hours 10.5 hours ⁴ 16 hours 13 hours Duration of filtration through filter B 7 hours 3 hours 19.5 hours 13 hours Total duration of the entire process (total holding time) 12.5 hours 17.5 hours 43.5 hours 29.5 hours Filter B full temperature range 10.4-12.2℃ controlled room temperature 10.2-11.7℃ controlled room temperature Temperature range after filter B 9.3-11.0℃ controlled room temperature 9.0-10.2℃ controlled room temperature Maximum pressure before filter B 0.6 bar 0.3 bar 0.6 bar 2.5 bar ⁵ Total volume filled with syringe 130L 50L 180L 134L Storage conditions during stability studies long term
(2-8℃)
Acceleration
(25℃/60%RH)
stress
(40℃/60%RH) stress
(40℃/60%RH) long term
(2-8℃)
Acceleration
(25℃/60%RH)
stress
(40℃/60%RH) long term
(2-8℃)
Acceleration
(25℃/60%RH)
stress
(40℃/60%RH) Stability data and conclusions The stability data have a similar stability profile in all three storage conditions, regardless of whether the drug product was filtered at controlled room temperature or under reduced pressure. Both filtration processes result in products with substantially identical degradation and impurity profiles under stress conditions.

1 Batch A and A-2 are from the same bulk solution. Filter B was replaced with a new filter before filtration of A-2.

2 Blending and subsequent holding time in the blending vessel (including filtration through filter A).

3 Start and fill time of filtration through filter B from the end of filtration through filter A.

Since A-2 is filtered and filled with a syringe following the filtration and filling of 4 A, the specified holding time is the sum of the holding time of A plus the time that A-2 is held until filtration is initiated at controlled room temperature. indicates.

5 Throughout the fill, a gradual increase in filtration pressure was required to maintain a flow rate commensurate with the rate required for continuous filling.

Based on the results of Experiment No. 3, it was confirmed that local cooling by the heat exchanger was sufficient to enable filtration of the 130L batch. It was also found that the quality and stability profiles of the filtered GA 40 mg/mL solution at controlled room temperature and reduced temperature were substantially the same.

Example 4

Cooling of the 40 mg/mL bulk solution of GA to less than 17.5° C. in the compounding vessel before passing through cooled filter A and then cooled filter B (see FIG. 6 ) maintains the same bulk solution within the compounding vessel and allows it to be controlled of both Filter A and Filter B compared to passing through Filter A and Filter B at room temperature (cooling of the bulk solution by using a double jacketed compounding vessel and cooling of the filter by using a double jacketed filter housing). This results in a lower pressure during the filtration step.

Reducing the temperature of the 40 mg/mL bulk solution of GA in the compounding vessel and passing it through cooled filter A and then filter B (see FIG. 6 ) was achieved not only by the total duration of the process (holding time), but also by keeping under controlled room temperature and Significantly reduces the filterability impairment caused by the larger filtration volume compared to the same filtered bulk solution.

Example 5

Local cooling of a 40 mg/mL bulk solution of GA by a heat exchanger followed by passage of the solution in the order of cooled filter A and then cooled filter B (see Figure 7) was compared to passage of the same bulk solution maintained and filtered under controlled room temperature. This results in a lower pressure during the filtration phase of both filter A and filter B.

The temperature reduction of the GA 40 mg/mL bulk solution using a heat exchanger and passing it through cooled filter A and then cooled filter B in that order (see Figure 7) was controlled not only by the total duration (holding time) of the process, but also at room temperature controlled Significantly reduces filterability impairment caused by a larger filtration volume compared to the same bulk solution maintained and filtered under

Example 6

The passage of sterile GA 40 mg/mL bulk solution from the receiving vessel through cooled filter B (see Figure 8) was significantly lower during the filtration step compared to the passage of the same bulk solution filtered through filter B under controlled room temperature. cause pressure

Passage of the sterile GA 40 mg/mL bulk solution from the receiving vessel through the cooled filter B (see FIG. 8) was performed with the same bulk solution maintained and filtered at room temperature controlled as well as by the total duration of the process (holding time). It significantly reduces filterability damage caused by filtering a comparatively larger volume.

Example 7

The passage of a 40 mg/mL bulk solution of GA from the compounding vessel in the order of cooled filter A and cooled filter B (see FIG. 9) was compared to the passage of the same bulk solution filtered under controlled room temperature for filtration of both filter A and filter B. This results in a lower pressure during the step.

The passage of 40 mg/mL bulk solution of GA from the receiving vessel in order of cooled filter A and filter B (see Figure 9) compared to the same bulk solution filtered under controlled room temperature as well as by the total duration (hold time) of the process. This significantly reduces filterability damage caused by filtering larger volumes.

Example 8

Cooling of the GA 40 mg/mL bulk solution to less than 17.5° C. in the compounding vessel before passing through filter A and filter B in sequence (see FIG. 10) maintains the same bulk solution within the compounding vessel and ensures that it is at controlled room temperature (double jacketed). This results in lower pressure during the filtration phase of both filter A and filter B compared to passing through filter A and filter B in the bulk solution (cooling of the bulk solution by using the combined vessel).

Decreasing the temperature of the 40 mg/mL bulk solution of GA in the compounding vessel and passing it through filter A and filter B in that order (see FIG. 10) resulted in the same bulk maintained at room temperature controlled as well as by the total duration (holding time) of the process. Significantly reduces filterability damage caused by larger filtration volumes compared to solutions.

Example 9

Cooling of the GA 40 mg/mL bulk solution to less than 17.5° C. in the receiving vessel prior to passing through filter B (see FIG. 11) is performed at a controlled room temperature (cooling of the bulk solution by using a double jacketed compounding vessel) in the compounding vessel. This results in a lower pressure during the filtration step of filter B compared to maintaining the same bulk solution in

The decrease in temperature of the 40 mg/mL bulk solution of GA in the receiving vessel (see Figure 10) was caused not only by the total duration of the process (holding time), but also by the larger filtration volume compared to the same bulk solution maintained under controlled room temperature. Significantly reduce the damage to the filterability.

Discussion of Examples 1-9

The temperature reduction of the GA 40 mg/mL sterile bulk solution significantly increases its filterability as evidenced by the much lower pressure increase on filter B during filtration and filling and by the larger volume that can be filtered at the reduced temperature. do. An increase in pressure was observed when the sterile bulk solution was maintained and filtered at controlled room temperature, while there was no significant increase in pressure when the solution was filtered under reduced temperature conditions.

The retention time of the bulk solution during filtration through filter B negatively affects the filterability of the solution. However, the total duration of the process (holding time) was significantly less impairing the filterability when the filtration was performed under reduced temperature conditions. Consequently, longer holding times can be used with reduced temperature filtration.

Both cooling of the solution by passage through a heat exchanger (local cooling) and/or cooling of the entire bulk (eg, by means of a double jacketed receiving vessel) prior to filtration through cooled filters A or B or A and B are reduced to a reduced temperature. It was found to be a suitable solution for filtration.

Accumulated stability data demonstrates that there are no substantial differences with respect to quality and stability profiles between solutions filtered under reduced temperature conditions and solutions filtered at controlled room temperature.

In summary, the experiments performed show that reduced temperature filtration through filter B significantly improves the filterability of the GA 40 mg/mL solution compared to the filterability of the solution when filtered at controlled room temperature. Moreover, decreasing the temperature of the bulk solution, or reducing the temperature of Filter A, during the compounding step or prior to passing through Filter A also improves the filterability of the GA 40 mg/mL solution compared to the filterability of the solution at controlled room temperature.

Consequently, the proposed preparation method for commercial batches of GA 20 mg/mL and GA 40 mg/mL involves cooling the solution prior to filtration of the bulk solution through filter B.

Example 10

container closure system

The container closure system selected for ^{Copaxone ®} 40 mg/mL is the same as that used for the ^{commercial product Copaxone ® 20 mg/mL PFS.} The container closure system consists of a colorless glass barrel, a plastic plunger rod and a gray rubber stopper.

* Long-term and accelerated stability studies

Satisfactory stability data can be used after storage for up to 36 months under long-term storage conditions (5°C±3°C) and after 6 months storage under accelerated conditions (25°±2°C/60±5%RH). The data demonstrate that the proposed container closure system is suitable for protection and maintenance of drug product quality throughout its proposed shelf life.

protection from light

Commercially available Copaxone ^® should be stored protected from light. Based on this recommendation, ^{it is proposed that Copaxone ®} 40 mg/mL is similarly packaged in PVC clear blisters inside a carton box that provides light protection. The light protection of the proposed packaging when used for Copaxone ^® 40 mg/mL is recommended according to the results obtained from a light stability study comparing the following packaging configurations:

1. Glass Barrel Syringe and Plunger Rod (First Package);

glass barrel syringes and plunger rods in clear blisters (partially in secondary packaging);

Glass barrel syringe and plunger rod (completely intended packaging configuration) in a clear blister inside the machine.

For reference, the following configuration was added:

2. Glass barrel syringe and plunger rod wrapped in aluminum foil;

Glass barrel and plunger rod in clear blister wrapped in aluminum foil.

All packages were simultaneously exposed to standardized sunlight for 10 days and near UV light for an additional 5 days.

All results obtained from photostability studies are within the specification. However, the impurity peak detected is lower when the drug product is packaged in its complete packaging configuration. The substrate has been shown to improve photostability and provide good light protection like aluminum foil, which is considered a complete light protector. The intended packaging configuration is therefore considered suitable for its use.

Storage instructions to protect the product from exposure should be appended to the product label.

microbiological properties

The drug product is a sterile, single dose, parenteral dosage form. Sterilization is accomplished by sterile filtration.

Microbial limit testing is performed on drug substances. Sterility and bacterial endotoxicity are monitored using pharmacopeia methods upon release of the drug product and throughout stability studies. The limits applied are the same as those applied for the ^{commercial Copaxone ® .}

The same container closure system is used for Copaxone ^® 20 mg/mL and Copaxone ^® 40 mg/mL. A preservation study study conducted to demonstrate the efficacy of a container closure system in use for a commercial product is also ^{considered relevant for Copaxone ®} 40 mg/mL.

Example 11

* Viscosity

The average viscosity of a batch of ^{Copaxone ®} 20 mg/mL filtered under controlled room temperature and that of a ^{batch of Copaxone ®} 40 mg/mL filtered under reduced temperature were obtained and compared. The average viscosity of the different batches of ^{Copaxone ®} 20 mg/mL filtered under controlled room temperature is reported in Table 5. The average viscosity of the different batches of ^{Copaxone ®} 40 mg/mL filtered under reduced temperature is reported in Table 6.

Copaxone filtered under controlled room temperature ^® Viscosity of 20 mg/mL batch batch number average viscosity [cPa] Standard Deviation One 1.92 ¹ 0.03 2 1.58 ¹ 0.00 3 1.58 ¹ 0.00 4 1.57 ¹ 0.00 5 1.67 ² 0.01 water for injection 0.93 ² 0.00 Average 1.664

1 Each value is the average of three separate results. Values are obtained using a Rheocalc V2.5 model LV, spindle CP40, speed 80 rpm, shear rate 600 1/sec, temperature 25° C.±0.1.

2 Each value is the average of 6 individual results. Values are obtained using a Rheocalc V2.5 model LV, spindle CP40, speed 80 rpm, shear rate 600 1/sec, temperature 25° C.±0.1.

Copaxone filtered under reduced temperature ^® Viscosity of 40 mg/mL batch batch number Average viscosity [cPa] ¹ Standard Deviation One 2.82 0.000 2 2.92 0.008 3 2.91 0.010 4 2.61 0.012 5 2.61 0.004 6 2.73 0.021 7 2.61 0.016 Average 2.743 0.007

1 Each value is the average of 6 individual results. Values are obtained using a Rheocalc V2.5 model LV, spindle CP40, speed 80 rpm, shear rate 600 1/sec, temperature 25° C.±0.1.

osmolality

The osmolality of the filtered Copaxone ^® 20 mg/mL batch ^{under controlled room temperature and the filtered Copaxone ®} 40 mg/mL batch under reduced temperature were measured.

Samples from each batch were tested in triplicate. The results are reported in Table 7.

filtered under controlled room temperature Copaxone ^® 20 mg/mL batch and reduced Copaxone filtered under temperature ^® Osmolality of 40 mg/mL batch batch number GA capacity mannitol dose average osmolality Relative standard deviation
(RSD) Copaxone ^® 40mg/mL
no. 1 40mg/ml 40mg/ml 303 mosmol/kg 1.2 Copaxone ^® 40mg/mL
No.2 40mg/ml 40mg/ml 300 ¹ mosmol/kg 1.7 Copaxone ^® 40mg/mL
number 3 40mg/ml 40mg/ml 302 mosmol/kg 2.1 Copaxone ^® 20mg/mL
no. 1 20mg/ml 40mg/ml 268 mosmol/kg 2.6 Copaxone ^® 20mg/mL
No.2 20mg/ml 40mg/ml 264 mosmol/kg 1.2 placebo 0mg/ml 40mg/ml 227 mosmol/kg 0

1 Calculated from 4 measurements.

The results indicate that ^{the osmolality of the Copaxone ®} 40 mg/mL batch was well within the range of the isotonic solution. The results also indicate that the Copaxone ^® 40 mg/mL batch is subject to the osmolality limit of a generic parenteral drug product of 300±30 mosmol/Kg. The results also indicate that the Copaxone ^® 20 mg/mL batch was slightly hypotonic.

Claims (43)

of glatiramer acetate and mannitol in a suitable container comprising the steps of
A method for preparing a pharmaceutical formulation:
(i) obtaining an aqueous pharmaceutical solution of glatiramer acetate and mannitol;
(ii) filtering the aqueous pharmaceutical solution at a temperature greater than 0° C. to 17.5° C. to prepare a filtrate; and
(iii) filling a suitable container with the filtrate obtained after performing step (ii) so as to prepare a pharmaceutical formulation of glatiramer acetate and mannitol in a suitable container, the suitable container being a syringe, vial, ampule , which is a cartridge or infusion. The method of claim 1 , wherein filtration step (ii) comprises filtering the aqueous pharmaceutical solution through a first filter, or a first filter and a second filter. 3. The method of claim 2, further comprising reducing the temperature of the second filter to a temperature of greater than 0°C to 17.5°C. 4. The method of claim 2 or 3, further comprising reducing the temperature of the aqueous pharmaceutical solution to a temperature of greater than 0°C to 17.5°C prior to passing through the second filter. 4. The method of claim 2 or 3, wherein the filtering step (ii) further comprises receiving the filtered aqueous pharmaceutical solution through a first filter in a receiving vessel. The method of claim 5 , further comprising reducing the temperature of the aqueous pharmaceutical solution to a temperature of greater than 0° C. to 17.5° C. after leaving the receiving vessel before entering the second filter. The method of claim 5 , further comprising reducing the temperature of the aqueous pharmaceutical solution to a temperature of greater than 0° C. to 17.5° C. while in the receiving vessel. 4. The method of claim 2 or 3, further comprising reducing the temperature of the first filter to a temperature of greater than 0°C to 17.5°C. 4. The method of claim 2 or 3, further comprising reducing the temperature of the aqueous pharmaceutical solution to a temperature of greater than 0° C. to 17.5° C. prior to passing through the first filter. 4. The method of claim 2 or 3, wherein obtaining step (i) comprises combining the aqueous pharmaceutical solution in a compounding vessel. The method of claim 10 , further comprising reducing the temperature of the aqueous pharmaceutical solution to a temperature of greater than 0° C. to 17.5° C. after leaving the compounding vessel and before entering the first filter. The method of claim 10 , further comprising reducing the temperature of the aqueous pharmaceutical solution to a temperature of greater than 0° C. to 17.5° C. while in the compounding vessel. 4. The method of claim 2 or 3, wherein the aqueous pharmaceutical solution is passed through the second filter at a rate of 3-25 liters/hour. 4. The method of claim 2 or 3, wherein the aqueous pharmaceutical solution is passed through the second filter at a rate of 3-22 liters/hour. 4. The method of claim 2 or 3, wherein the aqueous pharmaceutical solution is passed through the second filter at a rate of 3-15 liters/hour. 4. The method of claim 2 or 3, wherein the aqueous pharmaceutical solution is passed through the second filter at a rate of 3-10 liters/hour. 4. The process according to any one of claims 1 to 3, wherein the pressure during the filtering step (ii) and the pressure during the filling step (iii) are maintained at at least 0.3 bar and below 5.0 bar. 4. The process according to any one of claims 1 to 3, wherein the pressure during the filtering step (ii) and the pressure during the filling step (iii) are maintained at at least 0.3 bar and below 3.0 bar. 4. The process according to any one of claims 1 to 3, wherein the pressure during the filtering step (ii) and the pressure during the filling step (iii) are maintained at at least 0.3 bar and below 2.0 bar. 4. The method according to any one of claims 1 to 3, wherein the temperature of the aqueous pharmaceutical solution is between 0°C and 14°C, or the temperature of the aqueous pharmaceutical solution is reduced to a temperature of between 0°C and 14°C. 4. The method according to any one of claims 1 to 3, wherein the temperature of the aqueous pharmaceutical solution is between 0°C and 12°C, or the temperature of the aqueous pharmaceutical solution is reduced to a temperature of between 0°C and 12°C. 4. The method according to any one of claims 1 to 3, wherein the temperature of the aqueous pharmaceutical solution is 2°C-12°C, or the temperature of the aqueous pharmaceutical solution is reduced to 2°C-12°C. 4. The method according to any one of claims 1 to 3, wherein the temperature of the aqueous pharmaceutical solution is 4°C-12°C, or the temperature of the aqueous pharmaceutical solution is reduced to 4°C-12°C. 4. The filtration according to any one of claims 1 to 3, wherein the filtration is performed using a sterile filter having a pore size of 0.2 μm or less, wherein the first filter, the second filter or both filters have a pore size of 0.2 μm or less. A method that is a sterile filter. 4. The method according to any one of claims 1 to 3, wherein the pharmaceutical formulation in a suitable container is an aqueous pharmaceutical solution comprising 20 mg/ml of glatiramer acetate and 40 mg/ml of mannitol. 4. The method of any one of claims 1 to 3, wherein the pharmaceutical formulation in a suitable container is an aqueous pharmaceutical solution comprising 40 mg/ml of glatiramer acetate and 40 mg/ml of mannitol. 4. The method according to any one of claims 1 to 3, wherein the pharmaceutical formulation in a suitable container is an aqueous pharmaceutical solution having a pH in the range of 5.5-7.0. 4. The aqueous pharmaceutical solution according to any one of claims 1 to 3, wherein the pharmaceutical formulation in a suitable container is an aqueous pharmaceutical solution that is a sterile aqueous solution sterilized by filtration and has not been subjected to heat, chemical, or radiation exposure. how to be. 4. The method according to any one of claims 1 to 3, wherein the pharmaceutical formulation is a lyophilized powder of glatiramer acetate and mannitol. 4. The method of any one of claims 1 to 3, further comprising the step of lyophilizing the filtrate after filling into a suitable vessel to form a lyophilized powder of glatiramer acetate and mannitol in the suitable vessel. 4. The method according to any one of claims 1 to 3, wherein the suitable container is a syringe. 32. The method of claim 31, wherein the syringe contains 1 ml of the aqueous pharmaceutical solution. delete delete delete delete delete delete delete delete delete delete delete

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